Histone deacetylases (hdacs) inhibitors

ABSTRACT

Histone deacetylases inhibitors (HDACIs) and compositions comprising the same are disclosed. Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit are also disclosed.

REFERENCE TO RELATED APPLICATION

The present application claims the priority to U.S. ProvisionalApplication Ser. No. 61/622,127, filed Apr. 10, 2012, Which is hereinincorporated by reference in its entirety,

FIELD OF THE INVENTION

The present invention relates generally to histone deacetylasesinhibitors.

BACKGROUND OF THE INVENTION

WO2008040934, WO2008068170, WO/2008/087514, WO/2009/026446,WO12009/045440, WO/2011/011186, U.S. Pat. Nos. 8,188,138; 8,058,273, and7,803,800 disclose histone deacetylases (HDACs) inhibitors havingantitumor activities and antineurondegenerative activities,

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a compound having the structure

or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug,or a metabolite thereof,

wherein

-   -   R¹ is hydrogen (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl;    -   R² is (C₆-C₁₈)aryl, (C₆-C₁₈)aryl(C₁-C₆)alkyl,        (C₃-C₁₈)heteroaryl(C₁-C₆)alkyl, halo(C₆-C₁₈)aryl(C₁-C₆)alkyl, or        (C₁-C₆)alkoxy(C₆-C₁₈)aryl(C₁-C₆)alkyl;    -   R³ is hydrogen or N-hydroxyamino-oxo(C₂-C₆)alkenyl;    -   R⁴ is hydrogen, halogen. N-hydroxyamino-oxo(C₂-C₆)alkenyl, or        N-hydroxyaminocarbonyl(C₆-C₁₈)aryl(C₁-C₆)alkylene;    -   R⁵ is hydrogen, halogen, N-hydroxyamino-oxo(C₂-C₆)alkenyl,        N-hydroxyaminocarbonyl(C₆-C₁₈)aryl(C₁-C₆)alkylene, or        amino(C₆-C₁₈)aryl-oxo(C₂-C₆)alkenyl; and    -   R⁶ is hydrogen, N-hydroxyamino-oxo(C₂-C₆)alkenyl,        N-hydroxyamino(C₆-C₁₈)aryl (C₁-C₆ )alkylene or N-hydroxy amino        carbonyl(C₆-C₁₈)aryl(C₁-C₆)alkylene.

In one embodiment of the invention, wherein

-   -   R¹ is hydrogen, methyl, ethyl, cyclopropyl, or isopropyl;    -   R² is phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl,        2-(1H-indol-3-yl)ethyl, 2(4-fluorophenyl)ethyl, or        2-(4-methoxyphenyl)ethyl;    -   R³ is hydrogen or (2E)-3-N-hydroxyamino-3-oxo-propenyl;    -   R⁴ is hydrogen, fluoro, (2E)-3-N-hydroxyamino-3-oxo-propenyl, or        4-(N-hydroxyaminocarbonyl)benzyl;    -   R⁵ is hydrogen, chloro, fluoro,        (2E)-3-N-hydroxyamino-3-oxo-propenyl,        4-(N-hydroxyaminocarbonyl)benzyl, or        (2E)-3-N-(2-aminophenyl)-3-oxo-propenyl; and    -   R⁶ is hydrogen, (2E)-3-N-hydroxyamino-3-oxo-propenyl,        4-(N-hydroxyaminocarbonyl)phenyl, or        4-(N-hydroxyaminocarbonyl)benzyl, or a salt thereof.

In another embodiment of the invention, wherein

-   -   R¹ hydrogen, methyl, ethyl, cyclopropyl, or isopropyl;    -   R² is phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl,        2-(1H-indol-3-yl)ethyl, 2-(4-fluorophenyl)ethyl, or        2-(4-methoxyphenyl)ethyl;    -   R³ is hydrogen or (2E)-3-N-hydroxyamino-3-oxo-propenyl;    -   R⁴ is hydrogen, (2E)-3-N-hydroxyamino-3-oxo-propenyl, or        4-(N-hydroxyaminocarbonyl)benzyl;    -   R⁵ is hydrogen, (2E)-3-N-hydroxyamino-3-oxo-propenyl,        4-(N-hydroxyaminocarbonyl)benzyl, or        (2E)-3-N-(2-aminophenyl)-3-oxo-propenyl; and    -   R⁶ is hydrogen, (2E)-3-N-hydroxyamino-3-oxo-propenyl        4-(N-hydroxyaminocarbonyl)phenyl, or        4-(N-hydroxyaminocarbonyl)benzyl, or a salt thereof.

In another embodiment of the invention, wherein

-   -   R¹ is ethyl;    -   R² is 2-phenylethyl;    -   R³ is hydrogen;    -   R⁴ is fluoro;    -   R⁵ is (2E)-3-N-hydroxyamino-3-oxo-propenyl; and    -   R⁶ is hydrogen, or a salt thereof.

Further in another embodiment of the invention, wherein

-   -   R¹ is ethyl;    -   R² is 2-phenylethyl;    -   R³ is hydrogen;    -   R⁴ is (2E)-3-N-hydroxyamino-3-oxo-propenyl;    -   R⁵ is chloro or fluoro; and    -   R⁶ is hydrogen, or a salt thereof.

Further in another embodiment of the invention, the compound is selectedfrom the group consisting of(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-5-yl)-N-hydroxyacrylamide,(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-6-yl)-N-hydroxyacrylamide,(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenyquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-8-yl)-N-hydroxyacrylamide,(2E)-3-(3-benzyl-3,4-dihydro-2-methyl-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide.(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(3-(2-(1H-indol-3yl)ethyl)-3,4-dihydro-2-methyl-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide(2E)-3-(3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(2-ethyl-3,4-dihydro-4-oxo-3-(3-phenylpropyl)quinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(2-cyclopropyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3(3,4-dihydro-2-isopropyl-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3(3-(4-methoxyphenethyl)-2-ethyl-3,4-dihydro-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3(3-(4-fluorophenethyl)-2-ethyl-3,4-dihydro-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide,4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)methyl)-N-hydroxybenzamide,4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)methyl)-N-hydroxybenzamide,4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-8-yl)methyl)-N-hydroxybenzamide,4-(2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-8-yl)-N-hydroxybenzamideand(2E)-N-(2-aminophenyl)-3-(3,4-dihydro-2-methyl4-oxo-3-phenethylquinazolin-7-yl)acrylamide.

In another embodiment of the invention, the compound is(2E)-3-(2ethyl-6-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,or a salt thereof.

In another embodiment of the invention, the compound is(2E)-3-(2-ethyl-7-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide.(2E)-3-(7-chloro-2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide,or a salt thereof.

In another aspect, the invention relates to a composition comprising atherapeutically effective amount of a compound as aforementioned, or apharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or ametabolite thereof, and a pharmaceutically acceptable carrier orvehicle.

In another aspect the invention relates to a composition for use intreating a tumor disease associated with deregulation of the activity ofhistone deacetylases, wherein the composition comprises atherapeutically effective amount of a compound as aforementioned, or apharmaceutically acceptable salt a solvate or hydrate, a prodrug, or ametabolite thereof, and a pharmaceutically acceptable carrier orvehicle.

Further in another aspect, the invention relates to a composition foruse in treating a tumor disease associated with deregulation of theactivity of historic deacetylases as aforementioned, wherein the tumordisease is selected from the group consisting of pancreatic carcinoma,hepatocellular carcinoma, colon tumor, breast tumor, prostate tumor,lymphoma and cutaneous tumor.

In one embodiment of the invention, the cutaneous tumor disease isselected from melanomas and basal carcinomas.

In another aspect, the invention relates to a composition for use intreating a disease or condition wherein inhibition of HDAC provides abenefit, the composition comprising a therapeutically effective amountof a compound as aforementioned, or a pharmaceutically acceptable salt,a solvate or hydrate, a prodrug, or a metabolic thereof; and apharmaceutically acceptable carrier or vehicle.

Further in another aspect, the invention relates to a composition foruse in treating a neurodegenerative disease selected from the groupconsisting of Huntington's diseases (HD), Alzheimer's disease (AD).Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS),comprising a therapeutically effective amount of a compound asaforementioned, or a pharmaceutically acceptable salt, a solvate orhydrate, a prodrug, or a metabolite thereof, and a pharmaceuticallyacceptable carrier or vehicle.

Further in another aspect, the invention relates to a composition foruse in inhibiting the activity of histone deactylase (HDAC), thecomposition comprising an effective amount of a compound asaforementioned, or a pharmaceutically acceptable salt, a solvate orhydrate, a prodrug, or a metabolite thereof, and a pharmaceuticallyacceptable carrier or vehicle.

Yet in another aspect, the invention relates to a composition for use intreating a subject afflicted with breast cancer, colon cancer, largecell lung cancer, adenocarcinoma of the lung, small cell lung cancer,stomach cancer, liver cancer, ovary adenocarcinoma, pancreas carcinoma,prostate carcinoma, promylocytic leukemia, chronic myelocytic leukemia,or acute lymphocylic leukemia, the composition comprising atherapeutically effective amount of a compound as aforementioned, or apharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or ametabolite thereof, and a Pharmaceutically acceptable carrier orvehicle.

These and other aspects will become apparent from the followingdescription of the preferred embodiment taken in conjunction with thefollowing drawings, although variations and modifications therein may beaffected without departing from the spirit and scope of the novelconcepts of the disclosure.

The accompanying drawings illustrate one or more embodiments of theinvention and, together with the written description, serve to explainthe principles of the invention. Wherever possible the same referencenumbers are used throughout the drawings to refer to the same or likeelements of an embodiment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of rotarod test in Alzheimer's disease animalmodel treated with vehicle or compounds according to one embodiment ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. In the case of conflict, thepresent document, including definitions will control.

As used herein, “around”, “about;” or “approximately” shall generallymean within 20 percent, preferably within 10 percent, and morepreferably within 5 percent of a given value or range. Numericalquantities given herein are approximate, meaning that the term “around”,“about” or “approximately” can be interred if not expressly stated.

As used herein, the singular forms “a,” “an,” and “the” include pluralreference unless the context clearly dictates otherwise. It is furthernoted that the claims may be drafted to exclude any optional element. Assuch, this statement is intended to serve as antecedent basis for use ofsuch exclusive terminology as “solely,” “only,” and the like inconnection with the recitation of claim elements, or use of a “negative”limitation.

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only, they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

A dash (“—”) that is not between two letters or symbols is used toindicate a point of attachment for a moiety or substituent. For example,the moiety —CONH₂ is attached through the carbon atom.

The term “amino” refers to —NH₂. The amino group can be optionallysubstituted as defined herein for the term “substituted.”

The term “hydroxyamino” refers to —NHOH.

The term “alkyl” refers to a C₁-C₁₈ hydrocarbon containing normal,secondary, tertiary or cyclic carbon atoms. Examples are methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl (iso-butyl,—CH₂CH(CH₃(₂), 2butyl (sec-butyl, —CH(CH₃)CH₂CH₃), 2methyl-2-propyl(tert-butyl, —C(CH₃)₃), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl,3-methyl-2-butyl,3-methyl-1butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl,3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3pentyl, 2methyl-3pentyl, 2,3dimethyl-2butyl,3,3dimethyl-2butyl.

The alkyl can be a monovalent hydrocarbon radical, as described andexemplified above, or it can be a divalent hydrocarbon radical (i.e.,alkylene),

The term “alkenyl” refers to a C₂-C₁₈ hydrocarbon containing normal,secondary, tertiary or cyclic carbon atoms with at least one site ofunsaturation, i.e., a carbon-carbon, sp² double bond. Examples include,but are not limited to: ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂),cyclopentenyl (—C₅H₇), and 5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂). The alkenylcan be a monovalent hydrocarbon radical, as described and exemplifiedabove, or it can be a divalent hydrocarbon radical (i.e., alkenylene).

The term “alkylene” refers to a saturated, branched or straight chain orcyclic hydrocarbon radical of 1-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or different carbon atoms of a parent alkane. Typicalalkylene radicals include, but are not limited to methylene (—CH₂—)1,2-ethylene (—CH₂CH₂—), 1,3-propylene (—CH₂CH₂CH₂—), 1,4-butylene(—CH₂CH₂CH₂CH₂—), and the like.

The term “alkoxy” refers to the group alkyl-O—, where alkyl is definedherein. Preferred alkoxy groups include, e.g., methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexoxy, 1,2-dimethylbutoxy, and the like.

The term “aryl” refers to an unsaturated aromatic carbocyclic group offrom 6 to 20 carbon atoms having a single ring (e.g., phenyl) ormultiple condensed (fused) rings, wherein at least one ring is aromatic(e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Preferredaryls include phenyl, naphthyl and the like. The aryl can optionally hea divalent radical, thereby providing an arylene.

The aryl can optionally be substituted with one or more alkyl, alkenyl,alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl,heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino imino,alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,carboxy, carboxylalkyl, keto, thioxo, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamateisocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each R^(x) and R^(y) areindependently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,cycloalkyl, or hydroxy.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, an arylgroup bonded to an oxygen atom and an aralkyl group bonded to the oxygenatom at the alkyl moeity. Examples include but are not limited tophenoxy, naptithyloxy, and benzyloxy.

The term “carboxyl” refers to —COOH.

The phrase “compounds of the disclosure” refer to compounds of Formula(X) and pharmaceutically acceptable enantiomers, diastereomers, andsalts thereof. Similarly, references to intermediates, are meant toembrace their salts where the context so permits.

The “compound” refers to a chemical combination of two or more elementsthat may have an impact on any living system such as a cell, nerve ortissue.

The term “cycloalkyl” refers to gale alkyl groups of from 3 to 20 carbonatoms having a single cyclic ring or multiple condensed rings. Suchcycloalkyl groups include, by way of example, single ring structuressuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like,or multiple ring structures such as adamantanyl, and the like.

The cycloalkyl can optionally be substituted with one or more alkyl,alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl aryl,heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino,imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,carboxy, carboxylalkyl, keto, thioxo, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each R^(x) and R^(y) areindependently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,cycloalkyl, or hydroxy.

As used herein, the terms “halogen” or “halo” refer to fluoro, chloro,bromo, and iodo. Similarly, the term “halogen” refers to fluorine,chlorine, bromine, and iodine.

As used herein, the term “heteroaryl” is defined herein as a monocyclic,bicyclic, or tricyclic ring system containing one, two, or threearomatic rings and containing at least one nitrogen, oxygen, or sulfuratom in an aromatic ring, and which can be unsubstituted or substituted.The heteroaryl can optionally be a divalent radical, thereby providing aheteroarylene.

Examples of heteroaryl groups include, but are not limited to,2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4nH-carbazolyl, acridinyl,benzo[b,d]thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl,cinnaolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl,imidiolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl,isoquinalyl, isothiazolyl, isoxazolyl, naphthyridinyl, naptho[2,3-b],oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl,and xanthenyl. In one embodiment the term “heteroaryl” denotes amonocyclic aromatic ring containing five or six ring atoms containingcarbon and 1, 2, 3, or 4 heteroatoms independently selected from thegroup non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H,O, alkyl, phenyl, or benzyl. In another embodiment heteroaryl denotes anortho-fused bicyclic heterocycle of about eight to ten ring atomsderived therefrom, particularly a benz-derivative or one derived byfusing a propylene, or tetramethylene diradical thereto.

The heteroaryl can optionally be substituted with one or more alkyl,alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl,heteroaryl, heterocycle, cycloalkyl alkanoyl, alkoxycalbonyl, amino,imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl,alklysulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyannato sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each R^(x) and R^(y) areindependently H, alkyl, alkenyl, aryl heteroaryl, heterocycle,cycloalkyl, or hydroxy.

The term “hydrate” refers to the complex where the solvent is water.

The term “metabolite” refers to any compound of the Formula (X) producedin vivo or in vitro from the parent drug, or its prodrugs.

The term “oxo” refers to ═O.

The pharmaceutically acceptable salts of the compounds described hereincan be synthesized from the parent compound, which contains a basic oracidic moiety, by conventional chemical methods. Such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of many suitable salts are found in Remington: TheScience and Practice of Pharmacy, 21^(st) edition, Lippincott, Williams& Wilkins. (2005).

The term “prodrug” refers to any pharmaceutically acceptable form ofcompound of the Formula. (X), which, upon administration to a patient,provides a compound of the Formula (X). Pharmaceutically acceptableprodrugs refer to a compound that is metabolized, for example hydrolyzedor oxidized, in the host to form a compound of the Formula (X). Typicalexamples of prodrugs include compounds that have biologically labileprotecting groups on a functional moiety of the active compound.Prodrugs include compounds that can be oxidized, reduced, aminated,deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed,alkylated, dealklyated, acylated, deacylated, phosphorylated,dephosphorylated to produce the active compound.

The prodrug can be readily prepared from the compounds of Formula (X)using methods known in the art. See, e.g. See Notari, R. E., “Theory andPractice of Prodrug Kinetics,” Methods in Enzymology, 112:309 323(1985); Bodor, N., “Novel Approaches in Prodrug Design,” Drugs of theFuture, 6(3):165 182 (1981): and Bundgaard, H., “Design of Prodrugs:Bioreversible-Derivatives for Various Functional Groups and ChemicalEntities,” in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y.(.1985): Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed.,Vol. 1, pp. 172 178, 949 982 (1995).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute (in this invention, a compound of Formula X, or a salt orphysiologically functional derivative thereof) and a solvent. Suchsolvents, for the purpose of the invention, should not interfere withthe biological activity of the solute. Non-limiting examples of suitablesolvents include, but are not limited to water, methanol, ethanol, andacetic acid. Preferably the solvent used is a pharmaceuticallyacceptable solvent. Non-limiting examples of suitable pharmaceuticallyacceptable solvents include water, ethanol, and acetic acid.

The term “substituted” is intended to indicate that one or morehydrogens on the atom indicated in the expression using “substituted” isreplaced with a selection from the indicated group(s), provided that theindicated atom's normal valency is not exceeded, and that thesubstitution results in a stable compound. Suitable indicated groupsinclude, e.g., alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo,haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle,cycloalkyl, alkanoyl, acyloxy, alkoxycarbonyl, amino, imino, alkylamino,acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy,carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl,cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl,benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl,benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl,benzylthio, carbamoyl, carbamate, isocyanato, sulfamoyl, sulfinamoyl,sulfino, sulfo, sulfoamino, thiosulfo. NR^(x)R^(y) and/or COOR^(x),wherein each R^(x) and R^(y) are independently H, alkyl, alkenyl, aryl,heteroaryl, heterocycle, cycloalkyl, or hydroxy. When a substituent isoxo (i.e., ═O) or thioxo (i.e., =S) group, then two hydrogens on theatom are replaced.

Various forms are included in the embodiments, including polymorphs,solvates, hydrates, conformers, salts, and prodrug derivatives. Apolymorph is a composition having the same chemical formula, but adifferent structure. A solvate is a composition formed by solvation (thecombination of solvent molecules with molecules or ions of the solute).A hydrate is a compound formed by an incorporation of water.

Methods of making the Compounds of Formula (X)

The compounds described herein can be prepared by any of the applicabletechniques of organic synthesis. Many such techniques are well known inthe art. See e.g., “Compendium of Organic Synthetic Methods” (John Wiley& Sons, New York) Vol. 1, Ian T. Harrison and Shuyen Harrison (1971):Vol. 2, Ian T. Harrison and Shuyen Harrison (1974): Vol. 3, Louis S.Hegedus and Leroy Wade (1977); Vol, 4, Leroy G. Wade jr., (1980).Exemplary methods of making the compounds described herein are describedherein in the examples below.

Numerous modifications and variations of the presently disclosed subjectmatter are possible in light of the above teachings. It is to beunderstood that within the scope of the claims, the disclosed subjectmatter may be practiced otherwise than as specifically described herein.Specific ranges, values, and embodiments provided herein are forillustration purposes only and do not otherwise limit the scope of thedisclosed subject matter, as defined by the claims. The startingmaterials useful to synthesize the compounds of the present disclosureare known to those skilled in the art and can be readily manufactured orare commercially available.

The following methods set forth below are provided for illustrativepurposes and are not intended to limit the scope of the claimeddisclosure. It will be recognized that it may he necessary to preparesuch a compound in which a functional group is protected using aconventional protecting group then to remove the protecting group toprovide a compound of the present disclosure. The details concerning theuse of protecting groups in accordance with the present disclosure areknown to those skilled in the art.

Synthesis

The compounds of the general formula X are prepared by the followingprocedures of schemes:

EXAMPLE 1 Preparation ofN-Hydroxy-3-(2-methyl-4-oxo-3-phenyl-3,4-dihydro-quinazolin-6yl)-acrylamide (Compound 1b) Step 1: preparation of6-chloro-2-methyl-3-phenylquinazolin-4(3H)-one

5-chlomanthranilic acid (6 g, 34.27 mmol) mixed with triphenyl phosphite(11.1 mL, 41.08 mmol) in pyridine (25 mL) was added with acetyl chloride(3.7 mL, 51.33 mmol) and stirred at rt for 3 h. The resulting mixturewas added with aniline (4.7 mL, 51.47 mmol) and irradiated withmicrowave at 140° C. for 10 min. The reaction mixture was then dilutedwith ethyl acetate (50 mL) and washed with water (3×50 mL). The organicsolution was kept at rt to get solid formed, and the solution wasfiltered to get target compound as a white solid (5.32 g, 57.3%), ¹H NMR(400 MHz, DMSO-d₆) δ 2.10 (s, 3H). 7.43-7.45 (m, 2H), 7.51-7.58 (m, 3H),7.66 (d, J=8.8 Hz, 1H), 7.83 (dd, J=8.8, 0.4 Hz, 1H), 7.98 (d, J=2.4 Hz,1H), ^(—)C NMR (100 MHz, DMSO-d₆) 24.0, 121.7, 125.1, 128.2, 128.8,129.0, 129.5, 130.5, 134.5, 137.5, 145.9, 155.0, 160.3;

Step 2: preparation of (2E)-ethyl3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-6-yl)acrylate

The target solid of step 1 (4 g, 14.78 mmol), Herrmann's palladacycle(0.277 g, 0.30 mmol), and [(t-Bu)₃Ph]BF₄ (0.171 g, 0.60 mmol) mixed inDMF (40 mL) was added with ethyl acrylate (1.58 mL, 14.76 mmol) andCy₂NMe (3.27 mL, 14.78 mmol) and irradiated with microwave at 150° C.for 30 min (two times). The resulting mixture was evaporated to get darkgreen residue. The residue was suspended in ethyl acetate (50 mL) andwashed with water (3×50 mL). The organic layer dried over MgSO₄ wasevaporated to get crude yellow solid of target compound of step 2. Theyellow solid was put to step 3 without further purification.

Step 3: preparation of(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-6-yl)-N-hydroxyacrylamide(compound 1b)

NH₂OH.HCl (20.54 g, 69.49 mmol) suspended in methanol (28 mL) was addedwith solution of KOH (16.59 g, 295.67 mmol) dissolved in methanol (60mL), and the mixed solution was filtered and added dropwise for 20 minto solution of the yellow solid from step 2 suspended in methanol (40mL) under ice bath. Then the reaction mixture was stirred from ice bathto rt for 5 h. The resulting solution was poured to ice water (300 mL)and neutralized with 3N HCl (40 mL) to get solid formed. Then thesolution was filtered to get yellow solid. The solid was purified bycolumn chromatography eluting with 5% MeOH in CH₂Cl₂ to get compound 1bas white solid (1.42 g, 29.9%); mp 173-175° C. (dec); ¹H NMR (400 MHz,DMSO-d₆) δ 2.11 (s. 3H), 6.57 (d, J=15.6 Hz), 15.6 Hz), 7.44-7.60 (m,6H), 7.66 (d, J=8.4 Hz, 1H), 8.00 (dd, J=8.4, 1.6 Hz, 1H), 8.22 (d,J=1.6 Hz, 1H), 9.12 (br s, 1H), 10.79 (br s. 1H); ¹³C NMR (100 MHz,DMSO-d₆) δ 6) δ 24.1, 120.0, 120.7, 125.0, 127.3, 128.4, 129.0, 129.6,132.9, 133.3, 137.0, 137.7, 147.9, 155.2, 161.1, 162.4; ESIMS(−) m/z320.0 [M−1]⁻; Anal. (C₁₈H₁₅N₃O₃. 0.6 H₂O) C, H, N, Calcd: 65.09, 4.92,12,65, Found: 65.13, 5.01, 12.33,

EXAMPLE 2 Preparation of(2E)-3-(2-ethyl-6-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide(compound 2a) Step 1: Preparation ofN-(3-chloro-4-fluorophenyl)propionamide

3-chloro-4-fluoroaniline (10 g, 67.32 mmol) dissolved in CH₂Cl₂ wasadded with propionyl chloride (6.6 mL, 74.10 mmol) and triethyl amine(10.2 mL, 73.58 mmol) dropwise under water bath, and the mixture wasstirred for 2 h. The resulting solution was washed with water (2×50 mL)and saturated aqueous NaHCO₃ solution (12 mL). The CH₂Cl₂ layer driedover MgSO₄ was evaporated to give title compound as light purple solid(13.01 g, 96.3%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.06 (t, J=7.6 Hz, 3H),2.30 (q, J=7.6 Hz, 2H), 7.31 (dd, J=9.2 and 8.8 Hz, 1H), 7.44 (ddd,J=8.8 and 4 and 2.8 Hz, 1H), 7.91 (dd, J=7.2 and 2.8 Hz, 1H), 10.04 (brs, 1H),; ¹³C, NMR (100 MHz, DMSO-d₆) δ 9.4, 29.4, 116.6, 116.8, 118.8,119.0, 119.1, 120.2, 136.55, 136.58, 151.5, 153.9, 172.1;

Step 2 Preparation of N-(2-bromo-5-chloro-4-fluorophenyl)propionamide

The solid (10 g, 49.60 mmol) from step 1 dissolved in acetic acid (70mL) was added with Br₂ (12.7 mL, 247.93 mmol) dropwise for 2 h. Then thereaction mixture was kept stirring at rt for 5.5 h. The resultingmixture was poured to ice water (1L) and quenched with excess of NaHSO₃until the solution became clear with yellow suspension. The quenchedsolution was filtered to get title compound (13.52 g, 97.2%). ¹H NMR(400 MHz, DMSO-d₆) δ 1.07 (t, J=7.6 Hz, 3H), 2.36 (q, J=7.6 Hz, 2H),7.80 (d, J=7.6 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 9.50 (br s, 1H), ¹³NMR(100 MHz, DMSO-d₆) δ 10.1, 29.3, 117.3, 117.4, 119.0, 119.2, 121.0,121.2, 128.4, 134.45, 134,49, 153.4, 155,9, 173.0;

Step 3: preparation of 4-chloro-5-fluoro-2-(propionamide)benzoic acid

The solid (10 g, 35.65 mmol) from step 2 was mixed with Pd(OAc)₂ (0.288g, 1.28 mmol) and Xantphos (0.758 g, 1.28 mmol) in toluene (50 mL) andtriethyl amine (26.7 mL, 192.61 mmol) under Ar. The reaction vessel wasevacuated and followed by charging with CO to 1 atm. This cycle wasrepeated three times, and the solution was purged with CO gas for oneminute. The reaction mixture was stirred at 80° C. for 24 h. Theresulting mixture was injected with water (1 mL) and cooled to rt. Thesolution was diluted with ethyl acetate (100 mL) and filtered by celite.The filtered solution was extracted with a saturated aqueous NaHCO₃solution (2×25 mL). The aqueous NaHCO₃ solution was acidified with 3 NHCl to pH4 and filtered to get crude solid title compound (4.06 g). Thesolid was put to step 4 without further purification.

Step 4: Preparation of7-chloro-2-ethyl-6-fluoro-3-phenethylquinazolin-4(3H)-one

The crude solid (3 g) from step 3 above mixed with triphenyl phosphite(4 mL, 14.81 mmol) in pyridine (15 mL) was stirred at rt for 4 h. Themixture was added with phenethylamine (1.55 mL, 12.18 mmol), irradiatedwith microwave 250 W to refluxing for 15 min. The mixture was dilutedwith ethyl acetate (50 mL), washed with water (2×50 mL). The ethylacetated solution was mixed with water (50 mL) and kept at rt to givesolid form. The solution was filtered to give yellow solid titlecompound (1.1 g, 27.2%). mp=150-152° C. (recrystallized from ethylacetate); ¹H NMR (400 MHz, DMSO-d₆) δ 1.19 (t, J=7.2 Hz, 3H, CH₃), 2.76(q, J=7.2 Hz, 2H, CH₂), 2.93 (br t, J=7.6 Hz, 2H, CH₂), 4,19 (br t,J=7.6 Hz, 2H, CH₂), 7.20-7.31 (m, 5H, ArH), 7.80 (d, J=6.4 Hz, 1H, ArH),7.91 (d, J=8.8 Hz, 1H, ArH), ¹³C NMR (100 MHz, DMSO-d₆) δ 10.6, 26.9,33.5, 44.8, 112.2, 112.4, 119.8, 119.9, 126.6, 126.8, 127.0, 128.5,128.7, 128.8, 138.0, 144.1, 153.6, 156.1, 158.9, 160.0,; Anal.(C₁₈H₁₆ClFN₂O), C, H, N, Calcd: 65.36, 4.88, 8.47. Found: 65.09, 4.77,8.50.

Step 5: Preparation of (2E)-ethyl3-(2-ethyl-6-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)acrylate

The title compound was prepared using the procedure described in step 2of example 1. Yield 69.8%; R_(f)=0.28 (EA/Hexane=1:3); mp=140-142° C.(recrystallized from ethyl acetate/hexane); ¹H NMR (400 MHz, CDCl₃) δ1.30 (t, J=7.2 Hz, 3H, CH₃), 1.33 (t, J=7.2 Hz, 3H, CH₃), 2.66 (q, J=7.2Hz, 2H, CH₂), 3.00 ) (br t, J=7.6 Hz, 2H, CH₂), 4.24-4.30 (m, 4H, 2CH₂),6.67 (d, J=16.4 Hz, 1H, C═CH), 7.19-7.30 (m, 5H, ArH), 7.82 (d, J=16.4Hz, 1H, C═CH), 7.82 (d, J=6.8 Hz, 1H, ArH), 7.90 (d, J=10.4 Hz, 1H,ArH); ¹³C NMR (100 MHz, CDCl₃) δ 11.3, 14.4, 28.1, 34.8, 45.6, 61.0,112.3, 112.5, 122.3, 122.4, 123.9, 124.0, 127.1, 128.26, 128.29, 128.91,128.97, 129.4, 129.6, 136.24, 136.27, 137.8, 144.02, 144.04, 157.60,157.68, 160.2, 161.1, 161.2, 166.4,; Anal. (C₂₃H₂₃FN2O₃) C, H, N, Caled:70.04, 5.88, 7.10. Found: 70.02, 5.85, 7.10.

Step 6: Preparation of(2E)-3-(2-ethyl-6-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide(compound 2a)

The title compound was prepared using the procedure described in step 3of example 1. Yield 45.5%; R_(f)=0.24(MeOH/CHCl₃=1:9); mp=219-221° C.(dcc); ¹H NMR (400 MHz, DMSO-d₆) δ 1.20 (t, J=7.2 Hz, 3H), 2.76 (q,J=7.2 Hz, 2H), 2.94 (dd, J=7.6 Hz, 2H), 4.20 (dd, J=7.6 Hz, 2H), 6.77(d, J=16 Hz, 1H), 7.21-7.32 (m, 5H), 7.55 (d, J=16 Hz, 1H), 7.80 (d,J=6.8 Hz, 1H), 7.84 (d, J=6.4 Hz, 1H), 9.21 (br s, 1H), 10.91 (br s,1H); ¹³C, NMR (100 MHz, DMSO-d₆) δ 10.6, 26.8, 33.5, 44.7, 111.5 (d,J=24.0 Hz), 120.9 (d, J=9.0 Hz), 125.2 (d, J=6.0 Hz), 126.5, 127.9 (brs), 128.5, 128.7, 129.4 (d, J=15.0 Hz), 129.8, 138.1, 143.6, 157.8 (d,J=248.0 Hz), 157.9, 159.0, 160.0, 160.1, 161.8; ESIMS(−) m/z 380.0[M−1]⁻; Anal. (C₂₃H₂₀FN₃O₃. 1/10 C, H, N, Calcd: 65.82, 5.31, 10.97.Found: 65.50, 5.29, 10.75.

EXAMPLE 3 Preparation of(2E)-3-(2-ethyl-7-fluoro-3,4-dihydro-4-oxy-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide(3a)

Step 1: preparation of 2-amino-4-fluoro-5-iodobenzoic acid

4-fluoroanthranilic acid (1 g, 6.32 mmol) mixed with NalO₄ (1.35 g, 6.31mmol) and NaCl (0.74 g, 12.66 mmol) in acetic acid (18 mL) was addeddropwise with KI (1.05 g, 6.33 mmol) dissolved in water (2 mL) for 5min. The reaction mixture was kept stirring at rt for 8.5 h. The productmixture was poured on 100 mL of ice water and quenched with excess ofNaHSO₃ until the solution became clear with suspension. The solution wasfiltered, washed with water (200 mL) to give brown solid (1.17 g,65.9%). ¹H NMR (400 MHz, DMSO-d₆) δ 6.60 (d, J=10.8 Hz, 1H, ArH), 8.01(d, J=7.2 Hz, 1H, ArH),; ¹³C NMR (100 MHz, DMSO-d₆) δ 62.1, 62.3, 101.9,102.1, 109.2, 141.7, 141.8,153.3, 153.4, 162.6, 165.1, 167.6.

Step 2: preparation of2-ethyl-7-fluoro-6-iodo-3-phenethylquinazolin-4(3H)-one

The title compound was prepared using the procedure described in step 1of example 1. Yield 81.8%; R_(f)=0.57 (EA/Hexane=1:2); ¹H NMR (400 MHz,CDCl₃) δ 1.23 (t, J=7.2 Hz, 3H, CH₃), 2.58 (q, J=7.2 Hz, 2H, CH₂), 2.94(br t, J=7.6 Hz, 2H, CH₂), 4.20 (br t, J=7.6 Hz, 2H, CH₂), 7.13-7.26 (m,6H, ArH), 8.62 (d, J=6.8 Hz, 1H, ArH), ¹³C NMR. (100 MHz, CDCl₃) δ 10.1,27.2, 33.6, 44.5, 78.4, 78.7, 111.3, 111.5, 117.7, 117.8, 125.9, 127.7,127.8, 136.6, 137.41, 137.45, 148.1, 148.2, 1.58.5, 159.1, 162.4, 164.9.

Step 3: preparation of (2E)-ethyl3-(2-ethyl-7-fluoro-3,4-hydro-4-oxo-3-phenethylquinazolin-6-yl)acrylate

The title compound was prepared using a similar procedure described instep 2 of example 1 to get oil residue, which was used as a startingmaterial in step 4 below.

Step 4: Preparation of(2E)-3-(2-ethyl-7-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide(3a)

The title compound was prepared from the oil residue of step 3 using thesimilar procedure described above of the step 3 of example 1 to givecompound 3a as red solid (36.7%, step 2 and step 3);R_(f)=0.42(MeOH/CHCl₃=1:9): mp 183-185° C. (dec) (recrystallized frommethanol); ¹H NMR (400 MHz, DMSO-d₆) δ 1.19 (t, J=6.0 Hz, 3H), 2.76 (m,2H), 2.94 (m, 2H), 4.20 (m, 2H), 6.65 (d, J=16 Hz, 1H), 7.21-7.32 (m,5H), 7.39 (d, J=12.0 Hz, 1H), 7.54 (d, J=16 Hz, 1H), 8.31 (d, J=8.4 Hz,1H), 9.17 (br s, 1H), 10.87 (br s, 1H), ¹³C NMR (100 MHz, DMSO-d₆) δ10.6, 27.1, 33.5, 44.6, 112.4 (d, J=22.0 Hz), 117.1, 121.9 (d, J=14.0Hz), 122.7 (d, J=6.0 Hz), 126.6, 127.4 (d, J=5.0 Hz), 128.5, 128.7,129.7, 138.1, 148.9 (d, J=14.0 Hz), 160.0, 160.2, 160.2, 162.0, 163.5(d, J=255.0 Hz); ESIMS(−) m/z 380.0 [M−1]⁻. Anal. (C₂₁H₂₀FN₃O₃) C, H, N,Calcd: 66.13, 5.29, 11.02. Found: 66.05, 5.15, 10.76.

EXAMPLE 4 Preparation of4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-8-yl)methyl)-N-hydroxybenzamide(Compound 4c) Step 1: preparation of8-chloro-2-ethyl-3-phenethylquinazolin-4(3H)-one

The title compound was prepared using the procedure described above ofthe step 1 of example 1 from 3-chloroanthranilic acid (5 g, 29.14 mmol)to give white needle crystal (4.3 g, 47.2%): R_(f)=0.53 (EA/Hexane=1:2),¹H NMR (400 MHz, DMSO-₆) δ 1.24 (t, J=7.2 Hz, 3H), 2.79 (q, J=7.2 Hz,2H), 2.94 (t, J=7.6 Hz, 2H), 4.20 (t, J=7.6 Hz, 2H), 7.20-7.31 (m, 5H),7.41 (dd, J=8.0 7.6 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 8.05 (d, J=8.0 Hz,1H), ¹³C NMR (100 MHz, DMSO-d₆) δ 10.5, 27.1, 33.5, 44.7, 121.4, 125.2,126.4, 126.5, 128.5, 128.7, 130.3, 134.1, 138.1, 143.1, 158.7, 160.5,;Anal. (C₁₈H₁₇ClN₂O), C, H, N, Calcd: 69.12, 5.48, 8.96, Found: 69.11,5.38, 8.94.

Step 2: preparation of ethyl4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-8-yl)methyl)benzoate

The solid (2.8 g, 8.95 mmol) from step 1 mixed with Pd₂(dba)₃ (0.169 g,0.18 mmol) and [(t-Bu)PH]BF₄ (0.207 g, 0.71 mmol) in NMP (20 mL) wasadded at rt with mixture of Zn (0.64 g, 9.79 mmol) and ethyl4-(bromomethyl)benzoate (2.28 g, 9.47 mmol) prestirred at rt for 5 h.Then the reaction mixture was irradiated with microwave 250 W at 175° C.for 25 min. The resulting mixture was applied to column chromatographyeluting with EA/Hexane (1:4) to give title compound as white solid (1.84g, 44.1%).

Steps 3-5: Preparation of4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-8-yl)methyl)-N-hydroxybenzamide(Compound 4c)

The white solid (1.3 g, 2.95 mmol) of step 2, dissolved in mixture ofTHF (20 mL) and MeOH (4 mL) was added with aqueous LiOH solution (2.5 M)and stirred at rt for 24 h. The resulting solution was evaporated todry, suspended in water (100 mL), and acidified with 1 N HCl to pH3 toget precipitate formed. The solution was filtered to give white solid.Then the solid mixed with NH₂OBn.HCl (0.52 g, 3.26 mmol), EDCl (0.62 g,3.24 mmol), HOBt (0.45 g, 3.26 mmol), and triethyl amine (0.45 mL, 3.25mmol) in CH₂Cl₂ (30 mL) was stirred at rt for 15 h. After 15 h, thereaction mixture was evaporated to dry and suspended in EA (50 mL). TheEA solution was washed with water (3×50 mL), and the EA layer dried overMgSO₄ was evaporated to get beige solid. The beige solid was mixed withpalladium on charcoal (10%, 0.13 g) in mixture of MeOH (21 mL) and THF(7 mL) under Ar. The reaction vessel was evacuated and followed bycharging with H₂ to 1 atm. This cycle was repeated three times. Then thereaction mixture was stirred for 3 h at rt under H₂. After 3 h, theresulting mixture was filtered by celite, and the filtrate was purifiedby column chromatography to give compound 4c as white solid (0.62 g,three steps 49.1%).; R_(f)=0.37 (MeOH/CHCl₃=1:9); mp=204-206° C. (dec)(recrystallized from methanol/acetonitrile); ¹H NMR (400 MHz, DMSO-d₆) δ1.24 (t, J=7.2 Hz, 3H), 2.81 (q, J=7.2 Hz, 2H), 2.94 (dd, J=8.0 Hz, 2H),4.20 (dd, J=8.0 Hz, 2H), 4.38 (s, 2H), 7.25-7.43 (m, 8H), 7.61-7.63 (m,2H), 7.72 (dd, J=7.2 and 1.2 Hz, 1H), 8.01 (dd, J=8.0 and 1.2 Hz, 1H),8.94 (br s, 1H), 11.08 (br s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 10.5,26.9, 33.6, 35.6, 44.5, 120.1, 124.5, 126.0, 126.5, 126.8, 128.5, 128.6,128.7, 130.3, 134.5, 137.6, 138.2, 144.6, 144.7, 156.8, 161.2, 164.1;ESIMS(−) m/z 426.0 [M−1]⁻. Anal. (C₂₆H₂₅N₃O₃) C, H, N, Calcd: 73.05,5.89, 9.83. Found: 72.79, 5.81, 9.81.

EXAMPLE 5 Preparation of4-(2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-8-yl)-N-hydroxybenzamide(Compound 5a) Step 1 preparation of8-chloro-2-ethyl-3-phenethylquinazolin-4(3H)-one

The title compound was prepared using the procedure described above ofthe step 1 of example 1 from 3-chloroanthranilic acid (5 g, 29.14 mmol)to give white needle crystal (4.3 g, 47.2%); R_(f)=0.53 (EA/Hexane=1:2),¹H NMR (400 MHz, DMSO-d₆) δ 1.24 (t, J=7.2 Hz, 3H), 2.79 (q, J=7.2 Hz,2H), 2.94 (t, J=7.6 Hz, 2H), 4.20 (t, J=7.6 Hz. 2H), 7.20-7.31 (m. 5H),7.41 (dd, J=8.0, 7.6 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 8.05 (d, J=8.0 Hz,1H),; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.5, 27.1, 33.5, 44.7, 121.4, 125.2,126.4, 126.5, 128.5, 128.7, 130.3, 134.1, 138.1, 143.1, 158.7, 160.5.Anal. (C₁₈H₁₇CIN₂O) C, H, N. Calcd: 69.12, 5.48, 8.96, Found: 69.11,5.38, 8.94.

Step 2. Preparation of methyl4-(2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-8-yl)benzoate

The white crystal (3.7 g, 11.83 mmol) from step 1 mixed with Herrmann'spalladacycle (0.166 g, 0.18 mmol), [(t-Bu)PH]BF₄ (0.206 g, 0.71 mmol),cesium carbonate (3.87 g, 11.82 mmol), and DBU (0.18 mL, 1.20 mmol) inDMF (30 mL) under Ar was added with 4-(carbomethoxy)phenylboronic acid(2.17 g, 11.82 mmol). The reaction mixture was irradiated with microwave120 W to reflux for 20 min. After irradiation, the resulting mixture wasevaporated to get oil residue. The residue suspended in EA (50 ml,) waswashed with water (3×50 mL). The EA layer dried over MgSO4 wasevaporated to give title compound as beige solid (2.57 g, 52.7%).R_(f)=0.11 (EA/Hexane=1:4); ¹H NMR (400 MHz, CDCl₃) δ 1.14 (t, J=7.2 Hz,3H), 2.62 (q, J=7.2 Hz, 2H), 2.97 (dd, J=7.6 Hz, 2H), 4.23 (dd, J=7.6Hz, 2H), 7.18-7.27 (m, 5H), 7.45 (t, J=7.6 Hz, 1H), 7.69-7.71 (m, 2H),7.74 (dd, J=7.6 and 1.2 Hz, 1H), 8.03-8.05 (m, 2H), 8.28 (dd, J=8.0 and1.6 Hz, 1H), ¹³C NMR (100 MHz, CDCl₃) δ 10.7, 28.0, 34.7, 45.3, 52.1,121.2, 126.2, 126.9 (2C), 127.2, 128.7, 128.83, 128.85, 128.9, 130.2,130.7, 134.8, 137.5, 138.0, 143.2, 144.3, 156.4, 162.3, 167.2,;

Steps 3-5: Preparation of4-(2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-8-yl)-N-hydroxybenzamide(Compound 5a)

The title compound 5a was prepared using the procedure described aboveof the step 3, step 4, and step 5 of example 4 from the beige solid (2g, 4.85 mmol) of step 2 of example 5 to give compound 5a (0.199 g, threesteps 49.4%) as white solid. R_(f)=0.36 (MeOH/CHCl₃=1:9): mp=202-204° C.(dec) (reelystallized from dichloromethane); ¹H NMR (400 MHz, DMSO-d₆) δ1.10 (t, J=7.2 Hz, 3H), 2.76 (q, J=7.2 Hz, 2H), 2.96 (dd, J=7.6 Hz, 2H),4.23 (dd, J=7.6 Hz, 2H), 7.21-7.33 (m, 5H), 7.57 (dd, J=7.6 Hz, 1H),7.75-7.83 (m, 4H), 7.87 (br d, J=6.4 Hz, 1H), 8.18 (br d, J=6.8 Hz, 1H),9.04 (br s, 1H), 11.27 (br s, 1H): ¹³C NMR (100 MHz, DMSO-d₆) δ 10.4,27.0, 33.6, 44.5, 120.6, 126.1, 126.2, 126.5, 128.5, 128.7, 130.3,131.3, 134.7, 136.7, 138.2, 140.7, 143.7, 157.1, 161.1, 164.0,; ESIMS(−)m/z 412.0 [M−1]⁻. Anal. (C₂₅H₂₃N₃O₃. 1/10 H₂O) C, H, N. Calcd: 72.31,5.63, 10.12. Found: 72.10, 5.58, 9.93.

EXAMPLE 6 Preparation of(2E)-N-(2-aminophenyl)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenethylquinazolin-7-yl)acrylamide(Compound 6a) Step 1: preparation of7-chloro-2-methyl-3-phenethylquinazolin-4(3H)-one

4-chloroanthranilic acid (6 g, 34.27 mmol) suspended in acetic anhydride(25 mL, 264.47 mmol) was refluxed for 3 h. The resulting solution wascooled to rt to give crystal formed. The solution was filtered andwashed with excess of hexane to get light yellow needle crystal. Thecrystal was mixed with phenethylamine (4.6 mL, 36.15 mmol) in aceticacid (25 mL) and refluxed for 18.5 h. After 18.5 h, the reaction mixturewas diluted with dichloromethane (50 mL) and washed with water (3×50 mL)and saturated aqueous NaHCO₃ solution (7×40 mL). The organic layer driedover MgSO₄ was concentrated to around 20 mL and added with excess ofMeOH to get crystal formed. The solution was filtered to give titlecompound as white crystal (5.2 g, 50.8%). R_(f)=0.3 (ethylacetate/hexane=1:2); mp 133-135° C. (recrystallized from methanol); ¹HNMR (400 MHz, DMSO-d₆) δ 2.46 (s, 3H, CH₃), 2.96 (t, J=8 Hz, 2H, CH₂),4.20 (t, J=8 Hz, 2H, CH₂), 7.23-7.25 (m, 3H, ArH). 7.28-7.32 (m, 2H,ArH), 7.49 (dd, 1H, J=8.4, 2 Hz, ArH), 7.60 (d, J=2 Hz, 1H, ArH), 8.09(d, J=8.4 Hz, 1H, ArH), ¹³C NMR (50 MHz, DMSO-d₆) δ 23.2, 33.9, 46.2,119.2, 126.1, 127.0, 127.1, 128.7, 129.1, 129.3, 138.7, 139.4, 148.6,157.1, 160.9; ESIMS(+) m/z 299.0 [M+1]⁺. Anal. (C₁₇H₁₅ClN₂O) C, H, N.Calcd, 68.34, 5.06, 9.38, Found: 68.56, 5.07, 9.57.

Step 2: Preparing (2E)-ethyl3-(3,4-dihydro-2-methyl-4-oxo-3-phenethylquinazolin-7-yl)acrylate

The title compound was prepared using the similar procedure describedabove of the step 2 of example 1 from the beige solid (4.5 g, 15.06mmol) of title compound of step 1 of example 6 to give light yellowsolid (3.5 g, 64.1%). R_(f)=0.2 (ethylacetale/hexane=1:2), trip 149-151°C. (recrystallized from ethylacetate), ¹H NMR (400 MHz, DMSO-d₆) δ 1.26(t, J=7.2 Hz, 3H, CH₃), 2.47 (s, 3H, CH₃), 2.96 (t, J=8 Hz, 2H, CH₂),4.18-4.23 (m, 4H, CH₂), 6.81 (d, J=16 Hz, 1H, C═CH), 7.23-7.33 (m, 5H,ArH), 7.76 (d, J=16 Hz, 1H, C═CH), 7.82-7.86 (m, 2H, ArH), 8.09 (d. J=8Hz, 1H, ArH), ¹³C NMR (100 MHz, DMSO-d₆) δ 14.1, 22.6, 33.4, 45.6, 60.2,120.7, 121.1, 124.8, 126.5, 126.6, 127.0, 128.5, 128.7, 138.2, 139.5,143.0, 147.3, 155.6, 160.6, 165.8; ESIMS(+) m/z 363.1 [M+1]⁺. Anal.(C₂₂H₂₂N₂O₃) C, H. N. Calcd: 72.91, 6.12, 7.73. Found: 72.73, 6.09,7.86.

Steps 3-4: Preparing(2E)-N-(2-aminophenyl)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenethylquinazolin-7-yl)acrylamide(Compound 6a)

The solid (1 g, 2.76 mmol) from step 2 was mixed with aqueous LiOH (2.5M) in mixture of THF (20 mL) and MeOH (4 mL) and stirred at rt for 1.5h. The resulting solution was poured to ice water (50 mL) and acidifiedwith 3 N HCl (3 mL) to pH1. Then the solution was filtered to get crudewhite solid. Then the solid dissolved in THF (20 mL) was added with EDCI(0.66 g, 3.37 mmol) and stirred at rt for 45 min. Then1,2-diaminobenzene (2.11 g, 19.12 mmol) was added to the reactionmixture and kept stirring at rt for 24 h. After 24 h, the resultingmixture was evaporated to dry and suspended in EA (70 mL) and washedwith water (3×50 mL) and saturated aqueous NaHCO₃(4×30 mL). The organiclayer dried over MgSO₄ was evaporated to get yellow solid. The yellowsolid was suspended in MeOH (50 mL, and filtered to give compound 6a asyellow solid (0.707 g, two steps 69.7%). mp 246-248° C. (dec) (amorphousyellow solid); ¹H NMR (400 MHz, DMSO-d₆) δ 2.48 (s, 3H, CH₃), 2.97 (t,J=8 Hz, 2H, CH₂), 4.22 (t, J=8 Hz, 2H, CH₂), 4.97 (br s, 2H, NH₂), 6.58(t, J=7.6 Hz, 1H, ArH), 6.76 (d, J=8 Hz, 1H, ArH), 6.92 (t, J=7.6 Hz,1H, ArH), 7.09 (d, J=16 Hz, 1H, C═CH), 7.22-7.37 (m, 6H, ArH), 7.65-7.76(m, 3H, ArH, C═CH) 8.15 (d, J=8.4 Hz, 1H, ArH), 9.46 (hr s, 1H, NH); ¹³CNMR (100 MHz. DMSO-d₆) δ 22.7, 33.5, 45.6, 115.9, 116.2, 120.2, 123.2,124.2, 124.7, 125.4, 125.9, 126.2, 126.5, 126.8, 128.5, 128.7, 138.2,140.5, 141.6, 147.4, 155.6, 160.6, 163.0; ESIMS(+) m/z 425.1 [M+1]⁺;Anal. (C₂₆H₂₄N₄O₂. 0.4H₂O) C, H, N. Calcd: 72.34, 5.79, 12.98. Found:72.18, 5.76, 13.34.

Compounds Prepared using Similar Procedures Described in Scheme 1 andExample 1(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-5-yl)-N-hydroxyacrylamide(1a)

R_(f)=0.2 (MeOH/CHCl₃=1:9); mp 233-235° C. (dec); ¹H NMR (400 MHz,DMSOd₆) δ 2.28 (s, 3H), 6.34 (d, J=15.6 Hz, 1H), 7.47-7,69 (m, 6H),7.88-7.95 (m, 2H). 8.54 (d, J=16 Hz), ¹³C NMR (100 MHz, DMSO-d₆) δ 22.2,11.7.0, 122.8, 123.9, 126.5, 128.2, 129.6, 129.8, 135.1, 136.4, 137.6,137.8, 143.9, 157.9, 160.3, 162.2; ESIMS(+) m/z 322.1 [M+Na]⁺.

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-7-yl)-N-hydroxyacrylamide(1c)

R_(f)=0.45 (methanol/chloroform=1:5), mp 239-240° C. (dec)(recrystallized from methanol/acetonitrile); ¹H NMR (400 MHz, DMSO-d₆) δ2.11 (s, 3H), 6.67 (d, J=16.0 Hz, 1H), 7.42-7.68 (m, 7H), 7.78 (br s,1H), 8.07 (d, 8.0 Hz, 1H), 9.18 (br s, 1H), 10.90 (br s, 1H); ^(—)C NMR(100 MHz, DMSO-d₆) δ 624.0, 120.6, 122.3, 124.3, 126.1, 126.9, 128.4,128.9, 129.5, 137.1, 137.7, 140.7, 147.7, 155.1, 160.9, 162.1; ESIMS(−)m/z 320.0 [M−1]⁻. Anal. (C₁₈H₁₅N₃O₃) C, H, N. Calcd: 67.28, 4.71, 13.08.Found: 67.29, 4.87, 13.45,

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-8-yl)-N-hydroxyacrylamide(1d)

R_(f)=0.23 (MeOH/CHCl₃=1:9): mp=169-171° C. (dec). ¹H NMR (400 MHz,DMSO-d₆) δ 2.18 (s, 3H), 6.80 (d, J=16 Hz, 1H), 7.45-7.47 (m, 2H),7.50-7.59 (m, 4H), 8.06-8.11 (m, 2H), 8.32 (d, J=16 Hz, 1H), 9.08 (br s,1H), 10.86 (br s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 24.3, 121.1, 121.2,126.2, 127.4, 128.3, 129.0, 129.5, 130.9, 131.7, 133.5, 137.7, 145.1,154.4, 161.1, 162.8, ESIMS(−) m/z 320.0 [M−1]⁻. Anal (C₁₈H₁₅N₃O₃.⅓CHCl₃) C, H, N. Calcd: 60.98. 4.28, 11.64; Found. 61.23, 4.42, 11.65.

(2E)-3-(3-benzyl-3,4-dihydro-2-methyl-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide(1e)

R_(f)=0.45 (MeOH/CHCl₃=1:7); mp 216-218° C. (dec) (recrystallized frommethanol/acetonitrile); ¹H NMR (400 MHz, DMSO-d₆) δ 2.48 (s, 3H). 5.36(s, 2H), 6.66 (d, J=15.6 Hz, 1H), 7.18 (br d, J=7.6 Hz, 2H), 7,25-7.35(m, 3H), 7.59 (d, J=16 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.75 (br s, 1H),8.14 (d, J=8 Hz, 1H), 9.15 (br s, 1H), 10.87 (br s, 1H): ¹³C NMR (100MHz, DMSO-d₆) δ 22.9, 46.3, 120.0, 122.3, 124.4, 126.1, 126.3, 127.1,127.3, 128.8, 136.4, 137.1. 140.7, 147.5, 155.9, 161.1, 162.2; ESIMS(−)m/z 334.0 [M−1]⁻. Anal. (C₁₉H₁₇N₃O₃) C, H, N Calcd: 68.05, 5.11, 12.53,Found: 67.88, 5.06, 12.20.

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide(1f)

R_(f)=0.25 (methanol/chloroform=1:9); mp 227-229° C. (dcc)(recrystallized from methanol/acetonitrile); ¹H NMR (400 MHz, DMSO-d₆) δ2.45 (s, 3H). 2.96 (t, J=7.6 Hz), 4.21 (t, J=7.6 Hz, 2H), 6.66 (d, J=16Hz, 1H), 7.21-7.32 (m, 5H), 7.57 (d, J=16 Hz, 1H), 7.65 (d, J=8.4 Hz,1H). 7.70 (br s, 1H), 8.11 (d, J=8.4 Hz, 1H), 9.15 (br s, 1H), 10.90 (brs, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 22.6, 33.5, 45.6, 120.1, 122.2,124.1, 125.9, 126.5, 126.7, 128.5, 128.7, 137.0, 138.2, 140.4, 147.4,155.6, 160.6, 162.1; ESIMS(−) m/z 348.0 [M−1]⁻. Anal. (C₂₀H₁₉N₃O₃) C, H,N. Calcd: 68.75, 5.48, 12.03. Found: 68.81, 5.51, 12.17.

(2E)-3-(3-(2-(1H-indol-3-yl)ethyl)-3,4-dihydro-2-methyl-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide(1g)

R_(f)=0.38 (MeOH/CHCl₃=1:7); mp=° C. ¹H NMR (400 MHz, DMSO-d₆) δ2.47 (s,3H). 3.09 (t, J=7.6 Hz, 2H), 4.26 (t, J=7.6 Hz, 2H), 6.65 (d, J=15.6 Hz,1H), 6.97 (dd, J=7.6, 7.2 Hz, 1H), 7.07 (dd, J=7.6, 7.2 Hz, 1H), 7.17(d, J=2 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.56-7.70 (m, 4H), 8.15 (d,J=8.4 Hz, 1H), 9.16 (br s, 1H), 10.88 (br s, 2H): ¹³C NMR (100 MHz,DMSO-d₆) δ 22.7, 23.6, 45.1, 110.5, 111.4, 118.1, 118.4, 120.2, 121.1,122.1, 123.2, 124.1, 125.9, 126.8, 127.0, 136.2, 137.1, 140.4, 147.5,155.6, 160.7, 162.1; ESIMS(−) m/z 387.0 [M−1]⁻. Anal. (C₂₂H₂₀N₄O₃. 1.2H₂O) C, H, N. Calcd: 64.44, 5.51, 13.66. Found: 64.77, 5.51, 13.30.

(2E)-3-(3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide(1h)

R_(f)=0.33 (methanol/dichloromethane=1:19); mp 197-199° C. (dec)(recrystallized from methanol/acetonitrile); ¹H NMR (400 MHz, DMSO-d₆) δ3.00 (t, J=7.2 Hz, 2H), 4.19 (t, J=7.2 Hz, 2H), 6.69 (d, J=16 Hz, 1H),7.18-7.29 (m, 5H), 7.57 (d, J=15.6 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.76(br s, 1H), 8.13-8.18 (m, 2H), 9.16 (br s, 1), 10.95 (br s, 1H); ¹³C NMR(100 MHz, DMSO-d₆) δ 34.2, 47.4, 121.6, 122.5, 125.1, 126.4, 126.6,126.7, 128.5, 128.8, 136.9, 137.8, 140.5, 148.3, 148.5, 159.8, 162.1;ESIMS(−) m/z 334.0 [M−1]⁻. Anal. (C₁₉H₁₇N₃O₃. 1 H₂O) C, H, N. Calcd:64.58, 5.42, 11.89. Found: 64.57, 5.47, 11.55.

(2E)-3-(2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide(1i)

R_(f)=0.25 methanol/dichloromethane=9); mp 209-211° C. (recrystallizedfrom methanol/acetonitrile); ¹H NMR (400 MHz, DMSO-d₆) δ 1.21 (t, J=7.2Hz, 3H), 2.76 (q, J=7.2 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H), 4,20 (t, J=7.6Hz, 2H), 6.68 (d, J=16.0 Hz, 1H), 7.20-7.31 (m, 5H), 7.56 (d, J=16.0 Hz,1H), 7.64 (br d, J=8.4 Hz, 1H), 7.71 (br s, 1H), 8.10 (d, J=8.0 Hz, 1H),9.25 (br s, 1H), 10.84 (br s, 1H), ¹³C NMR (100 MHz, DMSO-d₆) δ 10.7,27.0, 33.6, 44.6, 120.0, 122.2, 124.3, 126.0, 126.5, 126.8, 128.5,128.7, 136.9, 138.2, 140.5, 147.2, 158.5, 160.7, 162.1: ESIMS(−) m/z362.1 [M−1]⁻. Anal. (C₂₁H₂₁N₃O₃) C, H, N. Calcd: 69.41, 5.82, 11.56.Found: 69.35, 5.79, 11.50.

(2E)-3-(2-ethyl-3,4-dihydro-4-oxo-3-(3-phenylpropyl)quinazolin-7-yl)-N-hydroxyacrylamide(1j)

R_(f)=0.25 (methanol/chloroform=1:9); mp=189-191° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 1.22 (t, J=7.2 Hz, 3H), 1.92 (p, J=7.6 Hz, 2H), 2.68 (dd,J=7.6 Hz, 2H), 2.77 (q, J=7.2 Hz, 2H), 4.00 (dd, J=7.6 Hz, 2H), 6.68 (d,J=15.6 Hz, 1H), 7.14-7.18 (m, 1H), 7.23-7.29 (m, 4H), 7.54 (d, J=15.6Hz, 1H), 7.62 (br d, J=8.0 Hz, 1H), 7.69 (br s, 1H), 8.06 (d, J=8.4 Hz,1H), ¹³C NMR (100 MHz, DMSO-d₆) δ 10.9, 27.0, 29.4, 32.4, 42.7, 120.0,122.3, 124.2, 125.9 (2C), 126.7, 128.2, 128.3, 136.8, 140.4, 140.9,147.2, 158.5, 160.7, 162.0; ESIMS(−) m/z 376.0 [M−1]⁻. Anal.(C₂₂H₂₃N₃O₃) C, H, N. Calcd: 70.01, 6.14, 11.13, Found: 69.74, 6.08,11.11.

(2E)-3-(2-cyclopropyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide(1k)

R_(f)=0.27 (MeOH/CHCl₃=1:9): mp=204-206° C. (dec) (recrystalized frommethanol/acetonitrile); ¹H NMR (400 MHz, DMSO-d₆) δ 1.01-1.10 (m, 4H),2.20-2.26 (m, 1H), 3.00 (dd, J=8.0 Hz, 2H), 4.43 (dd, J=8.0 Hz, 2H),6.64 (d, J=15.6 Hz, 1H), 7.20-7.31 (m, 5H), 7.54 (d, J=16 Hz, 1H),7.59-7.61 (m, 2H), 8.06 (d, J=8.4 Hz, 1H), 9.17 (br s, 1H), 10.85 (br s,1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 9.0 (2C), 13.6, 34.0, 44.5, 119.9,122.2, 124.0, 125.8, 126.5, 126.8, 128.5, 128.8, 137.1, 138.1, 140.4,147.4, 158.6, 160.7, 162.2; ESIMS(−) m/z 373.9 [M−1]⁻. Anal.(C₂₂H₂₁N₃O₃) C, H, N. Calcd: 70.38, 5.64, 11.29. Found: 70.41, 5.59,11.23.

(2E)-3-(3,4-dihydro-2-isopropyl-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide(1l)

R_(f)=0.27 (MeOH/CHCl₃=1:9), mp 173-174° C. (dec) (recrystallized frommethanol/acetonitrile); ¹H NMR (400 MHz, DMSO-d₆) δ 1.13 (d, J=6.4 Hz,6H), 2.93-3.00 (m, 3H, CH₂ and CH), 4.27 (dd, J=7.4 Hz, 2H), 6.67 (d,J=16 Hz, 1H), 7.18-7.29 (m, 5H), 7.57 (d, J=16 Hz, 1H), 7.65 (br d,J=8.4 Hz, 1H), 7.71 (br s, 1H), 8.12 (d, J=8.0 Hz, 1H), 9.16 (br s, 1H),10.85 (br s, 1); ¹³C NMR (100 MHz, DMSO-d₆) δ 21.1 (2C), 31.3, 34.1,44.2, 120.0, 122.3, 124.4, 126.0, 126.5, 126.8, 128.5, 128.8, 137.0,138.0, 140.5, 147.2, 160.9, 162.2, 161.3, ESIMS(−) m/z 376.0 [M−1]⁻.Anal. (C₂₂H₂₃N₃O₃) C, H, N. Calcd: 70.01, 6.14, 11.13. Found: 69.72,6.14, 11.04.

(2E)-3-(3-(4-methoxyphenethyl)-2-ethyl-3,4-dihydro-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide(1m)

R_(f)=0.32(MeOH/CHCl₃=1:9); mp=215-217° C. (recrystalized from); ¹H NMR(400 MHz, DMSO-d₆) δ 1.22 (t, J=7.2 Hz, 3H), 2.77 (q, J=7.2 Hz, 2H),2.87 (dd, J=7.6 Hz, 2H), 3.70 (s, 3H), 4.16 (dd, J=7.6 Hz, 2H), 6.65 (d,J=16 Hz, 1H), 6.85-6.87 (m, 2H), 7.14-7.16 (m, 2H), 7.57 (d, J=16 Hz,1H), 7.64 (br d, J=8.4 Hz, 1H), 7.72 (br s, 1H), 8.11 (d, J=8.0 Hz, 1H),9.15 (br s, 1H), 10.84 (br s, 1H): ^(—)C NMR (100 MHz, DMSO-d₆) δ 10.8,27.0, 32.8, 44.8, 55.0, 113.9, 120.0, 122.2, 124.3, 126.0, 126.7, 129.7,130.0, 137.0, 140.4, 147.2, 158.0, 158.5, 160.7, 162.1: ESIMS(−) m/z392.0 [M−1]⁻. Anal. (C₂₂H₂₃N₃O₄) C, H, N. Calcd: 67.16, 5.89, 10.68,Found: 66.78, 5.91, 10.33.

(2E)-3-(3-(4-fluorophenethyl)-2-ethyl-3,4-dihydro-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide(1n)

R_(f)=(MeOH/CHCl₃=1:9); mp=mp 195-197° C. (dec); ¹H NMR (400 MHz,DMSO-d₆) δ 1.23 (t, J=7.2 Hz, 3H), 2.79 (q, J=7.2 Hz, 2H), 2.94 (dd,J=7.2 Hz, 2H), 4.20 (dd, J=7.6 Hz, 2H), 6.65 (d, J=15.6 Hz, 1H),7.10-7.15 (m, 2H), 7.27-7.30 (m, 2H), 7.57 (d, J=16 Hz, 1H), 7.65 (br d,J=8.4 Hz, 1H), 7.73 (br s, 1H), 8.11 (d, J=8.4 Hz, 1H), 9.14 (br s, 1H).10.83 (br s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 10.8, 27.0, 32.8, 44.5,115.2 (d, J=21 Hz), 120.0, 122.1, 124.3, 126.0, 126.8, 130.6 (d, J=8Hz). 134.4 (d, J=3 Hz), 137.0, 140.3, 147.2, 158.5, 160.7, 161.0 (d,J=241 Hz), 162.1, ESIMS(−) m/z 379.9 [M−1]⁻. Anal. (C₂₃H₂₀FN₃O₃. 1/10H)) C, H, N. Calcd; 65.82, 5.31, 10.97. Found: 65.44, 5.11, 10.80.

Compounds Prepared using Similar Procedure Described in Scheme 3 andExample 3(2E)-3-(7-chloro-2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide(3b)

R_(f)=0.50 (MeOH/CHCl₃=1:9): mp=194-196° C. (recrystalized from); ¹H NMR(400 MHz, DMSO-d₆) δ 1.19 (t, J=7.2 Hz, 3H), 2.76 (q, J=7.2 Hz, 2H),2.95 (dd, J=7.6 Hz, 2H), 4.21 (dd, J=7.6 Hz, 2H), 6.64 (d, J=15.6 Hz,1H), 7.23-7.32 (m, 5H), 7.70 (s, 1H), 7.75 (d, J=16.0 Hz, 1H). 8.34 (s,1H), 9.21 (br s, 1H), 10.86 (br s, 1H): ¹³C NMR (100 MHz, DMSO-d₆) δ10.6, 27.1, 33.5, 44.7, 119.1, 122.9, 124.8, 126.6, 127.3, 128.5, 128.7,130.6, 132.4, 138.1, 138.6. 147.6, 160.1, 160.4, 161.8; ESIMS(−) m/z395.9 [M−1]⁻. Anal. (C₂₁H₂₀ClN₃O₃. H₂O) C, H, N. Calcd: 60.65, 5.33,10.10. Found: 60.52.

Compounds Prepared using Similar Procedure Described in Scheme 4 andExample 44-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)methyl)-N-hydroxybenzamide(4a)

R_(f)=0.27 (MeOH/CHCl₃=1:19); mp 181-183° C. (recrystallized frommethanol/acetonitrile); ¹H NMR (400 MHz, DMSO-d₆) δ 1.19 (t, J=7.2 Hz,3H), 2.74 (q, J=7.2 Hz, 2H), 2.92 (dd, J=7.6 Hz, 2H), 4.13 (s, 2H), 4.20(dd, J=7.6 Hz, 2H), 7.22-7.35 (m, 7H), 7.54 (d, J=8.4 Hz, 1H), 7.65-7.69(m, 3H), 7.95 (br s, 1H), 8.97 (br s, 1H), 11.13 (br s, 1H); ¹³C NMR(100 MHz, DMSO-d₆) δ 10.8, 26.8, 33.7, 40.2, 44.5, 119.7, 125.3, 126.5,127.0, 127.1, 128.5, 128.73, 128.78, 130.7, 135.1, 138.2, 139.1, 144. L145.3, 157.3, 161.0, 164.1; ESIMS (−) m/z 426.0 [M−1]⁻. Anal.(C₂₆H₂₅N₃O₃) C, H, N. Calcd: 73.05, 5.89, 9.83. Found: 72.82, 5.96,9.84.

4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)methyl)-N-hydroxybenzamide(4b)

R_(f)=0.26 (MeOH/CHCl₃=1:19); mp 181-183° C. (dec); ¹H NMR (400 MHz,DMSO-d₆) δ 1.11 (t, J=7.2 Hz, 3H), 2.63 (q, J=7.2 Hz, 2H), 2.88 (dd,J=7.6 Hz, 2H), 4.08 (s, 2H), 4.15 (dd, J=7.6 Hz, 2H), 7.15-7.26 (m, 5H),7.31-7.38 (m, 4H), 7.62-7.64 (m, 2H), 8.00 (d, J=8.0 Hz, 1H), 9.12 (brs, 1H), 11.22 (br s, 1); ¹³C NMR (100 MHz, DMSO-d₆) δ 11.4, 27.5, 3.1,41.2, 45.1, 118.4, 126.6, 126.9, 127.1, 127.7, 127.9, 129.1, 129.2,129.4, 131.0, 138.6, 144.4, 147.5, 148.3, 158.9, 161.7, 165.1; ESIMS(−)m/z 426.0 [M−1]⁻. Anal. (C₂₆H₂₅N₃O₃. ⅖ H₂O) C, H, N. Calcd: 71.84, 5.98,9.67. Found: 71.97, 5.95, 9.43.

HDAC Enzymatic Assay. These compounds had inhibitory effects on humanhistone deacetylases (HDAC) 1,2,3,6,8,10 and 11. The IC₅₀ values weredetermined using the following gradings: I˜IV, in which I stands forIC₅₀ being ≧10 mM: II stands for IC₅₀ being 1 μM but <10 μM; III standsfor IC₅₀ being >0.1 μM but <1 μM, and IV stands for IC₅₀ being ≦0.1 μM.The HDAC enzymatic assay method is known in the art. It was found thesecompounds inhibited HDAC1. HDAC6 and HDAC8 with respective IC50 asfollows: Compound Ia: I, IV and II, Compound Ib, 1m, 1n, 3a: II, IV andIII, Compound Id, 4c: I, III and III, Compounds Ic, Ie, If, Ii, Ij, 2a:II, IV and II. Compound 1g: III, IV, and II, Compound 1h: III, IV, andIII, Compound 2a, II, IV, and II, Compound 3b: I, III, and II, Compound4a: II, IV, and IV. Compound 6a: II, I, and I, respectively.

Compound 1k and 1l each showed inhibitions of HDAC1, HDAC6 with IC50 ofIII, and IV, respectively. The IC50 of Compound 4b against HDAC6 was IV.

Because compound 1b, 1c, 1e, 1f, 1g, 1h, 1i, 1j, 2a, 3a, 4a, 4b, and 4showed selective inhibitions on ITDAC6, the HDAC6-selective inhibitorsmay be used for treating autoimmunity, cancer, and manyneurodegenerative diseases. (S. Minucci et al., Nat Rev. Cancer. 2006,6, 38-51; L. Wang et al., Nat Rev. Drug Discov. 2009, 8, 969-81; J. P.Dompierre et al., J. Neurosci. 2007, 27, 3571-83; and A. G. Kazantsey etal., Nat. Rev. Drug Discover. 2008, 7, 854-68; all of which areincorporated herein by reference in its entireties.)

MTT or SRB assays for Cytotoxicities of HDAC inhibitors. These compoundswere assayed for cytotoxicities to the following cells: A549 cells(adenocarcinomic human alveolar basal epithelial cells), HCT-116 cells(human colon carcinoma cells). PANC-1 cells (human pancreatic carcinoma,epithelial-like cell line) and HepG2 cells (human liver hepatocellularcarcinoma cell line), neuronal cells PC12 (rat pheochromocytoma cellline) and SH-SY5Y (human neuroblastoma cell line). MTT(3-[4,5-dimethylthiazol-2-yl]2,5-diphenyl-tetrazolium bromide) reductionwas collaborated by using trypan blue exclusion assay.

The IC₅₀ values were determined using the following gradings: in whichI˜V in which I stands for IC₅₀ being ≧10 μM (non-toxic), II stands forIC-₅₀ being >1 μM but <10 μM (weak toxic), III stands for IC₅₀being >0.1 μM but <1 μM (toxic), and IV stands for IC₅₀ being ≦0.1 μM(higher toxic).

It was found that these compounds were nontoxic to neuronal and Verocells, but cytotoxic to cancer cells (A549, HCT116, PANC1 and HepG2sold-tumor cell lines) with respective gradings as follows: Compounds 1iand 4c: I, I, I, and II, Compounds 1m, 1n, 2a: II, II, II, and II,Compound 3a: II, I, I, I, Compound 3b: II, I, III, I, Compound 4b: II,II, II, III, Compound 5a: I, I, II, I, Compound 6a: I, I, III, III,respectively.

Neurite outgrowth assay. The effects of the compounds on neuriteoutgrowth were assayed on PC 12 and SH-SY5Y cells. It was found thesecompounds facilitated or promoted neurite outgrowth with EC50s (μM) asfollows: Compound 1c: 15.86±2.03 and 12.68±1.54. Compound 1e: 8.21±0.37and 8.20±0.92, Compound 1f: 6.49±0.78 and 6.77±0.96, Compound 1h:14.51±1.47 and 4.93±1.34, Compound 1i: 7,21±0.32 and 0.88±0.45, Compound1j: 6.95±0.82, 9.97±1,17, Compound 1k: 0.76±0.69, and >30, Compound 1l:5.28+0.51, and 6.74±0.78, Compound 1m: 20.62+3.12,, and 20.62±2.51,Compound 1n: 13.92±0.94, and 22.17±2.01, Compound 3b: 10.71±1.26, and7.63±0.74. Compound 4a: 2.89±0.45, and 4.06±0.58. Compound 6a:6.59±1.06, and 8.81±1.04 μM, respectively. Student's t test (p<0.005).Thus, these compounds may be used for treating neurodegenerativediseases.

Anti-amyloid aggregation assay. The effects of compounds on inhibitionof β-amyloid aggregation were assayed. The levels of β-amyloidaggregates were determined by thioilavin S. BCA or CR assays (Tables 1).Thioflavin S, and Congo red are for in “kitro staining of aggregatedβ-amyloid. Bicinchoninic acid (BCA) assay determines the total proteinlevel or concentration.

TABLE 1 IC₅₀ (μM) for zinc-mediated β-amyloid aggregation detected bythree different assays Compound # thioflavin S BCA CR 1a >50 10.1 30.21b >50 10.1 4.8 1c 18.4 11.1 44.1 1d >50 11.7 14.5 1e 18.1 10.6 5.8 1f9.5 11.7 43.1 1g 7.4 11.1 15.5 1h 5.5 35.0 14.6 1i 6.8 3.9 5.5 6a 10.713.8 30.9

Accordingly, the compounds of the invention may be useful for decreasingβ-amyloid aggregation toxicity, promoting neurite outgrowth, and in turnimproving the function of degenerating neurons.

Neurite synaptic uptake activity analysis. The effects of compounds onthe neuronal synapse uptake of fluorescent indicator FM1-43 wereassayed. The uptake of the dye indicated the synaptic function of theneurites. PC 12 and SH-SY5Y cells were used. Cells in experimentalgroups were treated with a test compound and FM1-43; Cells in positivecontrol were treated with NGF and FM1-43; Cells in negative control weretreated with a vehicle and FM1-43. The fluorescence in the positivecontrol were taken as 100%.

It was found that these compounds increased the uptake of dye by PC 12and SH-SY5Y cells with respective EC50 (μM) as follows: Compound 1a:8.15±0.39 and 14.73±1.58, compound 1c: 15.86±2.03 and 12.68±1.54,compound 1d: 7.81±0.65 and 8.03±0.53, compound 1e: 8.21±0.37 and8.20±0.92, compound 1f: 6.49±0.78 and 6.77±0.96, compound 1h: 14.51±1.47and 4.932±1.34, compound 1i: 7.21±0.32 and 0.88±0.45, compound 1j:6.95±0.82 and 9.97±1.17, compound 1k: 0.76±0.69 and >30, compound 1l:5.28±0.51, 6.74±0.78., compound 1m: 20.62±3.12 and 20.62±2.51. compound1n: 13.92±0.94 and 22.17±2.01. compound 3b: 10.71±1,26, 7.63±0.74,compound 4a: 2.89±0,45, 4.06±0.58. compound 6a: 6.59±1.06, 8.81±1.04μM,respectively. Compounds 2a, 3a, 4c increased the uptake of the dye by PC12 with an EC50 at 1.66±0.76, 0.78±0.49, and 5.34±0.85 (μM),respectively. The data indicated that these compounds facilitatedoutgrowth of neurites that have functional synapse uptake activities,which is important in terms of using these compounds for treatingneurodegenerative diseases and/or improving neurite functions inneurodegenerative diseases.

Rotarod test. To test the effect of the compound in improving thelearning ability of the animals in Alzheimer disease model,β-aggregates-induced hippocampal lesions were used to generatelearning-impaired mice. The hippocampus-lesioned mice were treated withcompound 1c and 1f (daily i.p. 10 mg/kg for 30 days). FIG. 1 shows theresults of rotarod test. Both compounds 1c and 1f improved learningperformance as compared to the controls (vehicle) inhippocampus-lesioned mice.

A compound having the structure of Formula X:

Formula X

Cpd Substituents of No. Chemical Name Structure Formula X 1a(2E)-3-(3,4-dihydro-2- methyl-4-oxo-3- phenylquinazolin-5-yl)-N-hydroxyacrylamide

R¹ = methyl R² = phenyl R³ = (2E)-3-N- hydroxyamino-3- oxo-propenyl R⁴ =hydrogen R⁵ = hydrogen R⁶ = hydrogen 1b (2E)-3-(3,4-dihydro-2-methyl-4-oxo-3- phenylquinazolin-6-yl)- N-hydroxyacrylamide

R¹ = methyl R² = phenyl R³ = hydrogen R⁴ = (2E)-3-N- hydroxyamino-3-oxo-propenyl R⁵ = hydrogen R⁶ = hydrogen 1c (2E)-3-(3,4-dihydro-2-methyl-4-oxo-3- phenylquinazolin-7-yl)- N-hydroxyacrylamide

R¹ = methyl R² = phenyl R³ = hydrogen R⁴ = hydrogen R⁵ = (2E)-3-N-hydroxyamino-3- oxo-propenyl R⁶ = hydrogen 1d (2E)-3-(3,4-dihydro-2-methyl-4-oxo-3- phenylquinazolin-8-yl)- N-hydroxyacrylamide

R¹ = methyl R² = phenyl R³ = hydrogen R⁴ = hydrogen R⁵ = hydrogen R⁶ =(2E)-3-N- hydroxyamino-3- oxo-propenyl 1e (2E)-3-(3-benzyl-3,4-dihydro-2-methyl-4- oxoquinazolin-7-yl)-N- hydroxyacrylamide

R¹ = methyl R² = benzyl R³ = hydrogen R⁴ = hydrogen R⁵ = (2E)-3-N-hydroxyamino-3- oxo-propenyl R⁶ = hydrogen 1f (2E)-3-(3,4-dihydro-2-methyl-4-oxo-3- phenethylquinazolin-7- yl)-N-hydroxyacrylamide

R¹ = methyl R² = 2-phenylethyl R³ = hydrogen R⁴ = hydrogen R⁵ =(2E)-3-N- hydroxyamino-3- oxo-propenyl R⁶ = hydrogen 1g(2E)-3-(3-(2-(1H-indol- 3-yl)ethyl)-3,4-dihydro- 2-methyl-4-oxoquinazolin-7-yl)-N- hydroxyacrylamide

R¹ = methyl R² = 2-(1H-indol-3- yl)ethyl R³ = hydrogen R⁴ = hydrogen R⁶= hydrogen 1h (2E)-3-(3,4-dihydro-4- oxo-3- phenethylquinazolin-7-yl)-N-hydroxyacrylamide

R¹ = hydrogen R² = 2-phenylethyl R³ = hydrogen R⁴ = hydrogen R⁵ =(2E)-3-N- hydroxyamino-3- oxo-propenyl R⁶ = hydrogen 1i(2E)-3-(2-ethyl-3,4- dihydro-4-oxo-3- phenethylquinazolin-7-yl)-N-hydroxyacrylamide

R¹ = ethyl R² = 2-phenylethyl R³ = hydrogen R⁴ = hydrogen R⁵ = (2E)-3-N-hydroxyamino-3- oxo-propenyl R⁶ = hydrogen 1j (2E)-3-(2-ethyl-3,4-dihydro-4-oxo-3-(3- phenylpropyl)quinazolin- 7-yl)-N- hydroxyacrylamide

R¹ = ethyl R² = 3-phenylpropyl R³ = hydrogen R⁴ = hydrogen R⁵ =(2E)-3-N- hydroxyamino-3- oxo-propenyl R⁶ = hydrogen 1k(2E)-3-(2-cyclopropyl- 3,4-dihydro-4-oxo-3- phenethylquinazolin-7-yl)-N-hydroxyacrylamide

R¹ = cyclopropyl R² = 2-phenylethyl R³ = hydrogen R⁴ = hydrogen R⁵ =(2E)-3-N- hydroxyamino-3- oxo-propenyl R⁶ = hydrogen 1l(2E)-3-(3,4-dihydro-2- isopropyl-4-oxo-3- phenethylquinazolin-7-yl)-N-hydroxyacrylamide

R¹ = isopropyl R² = 2-phenylethyl R³ = hydrogen R⁴ = hydrogen R⁵ =(2E)-3-N- hydroxyamino-3- oxo-propenyl R⁶ = hydrogen 1m (2E)-3-(3-(4-methoxyphenethyl)-2- ethyl-3,4-dihydro-4- oxoquinazolin-7-yl)-N-hydroxyacrylamide

R¹ = ethyl R² = 2-(4- methoxyphenyl)ethyl R³ = hydrogen R⁴ = hydrogen R⁵= (2E)-3-N- hydroxyamino-3- oxo-propenyl R⁶ = hydrogen 1n (2E)-3-(3-(4-fluorophenethyl)-2-ethyl- 3,4-dihydro-4- oxoquinazolin-7-yl)-N-hydroxyacrylamide

R¹ = ethyl R² = 2-(4- fluorophenyl)ethyl R³ = hydrogen R⁴ = hydrogen R⁵= (2E)-3-N- hydroxyamino-3- oxo-propenyl R⁶ = hydrogen 4a4-((2-ethyl-3,4-dihydro- 4-oxo-3- phenethylquinazolin-6- yl)methyl)-N-hydroxybenzamide

R¹ = ethyl R² = 2-phenylethyl R³ = hydrogen R⁴ = 4-(N-hydroxyaminocarbonyl) benzyl R⁵ = hydrogen R⁶ = hydrogen 4b4-((2-ethyl-3,4-dihydro- 4-oxo-3- phenethylquinazolin-7- yl)methyl)-N-hydroxybenzamide

R¹ = ethyl R² = 2-phenylethyl R³ = hydrogen R⁴ = hydrogen R⁵ = 4-(N-hydroxyaminocarbonyl) benzyl R⁶ = hydrogen 4c 4-((2-ethyl-3,4-dihydro-4-oxo-3- phenethylquinazolin-8- yl)methyl)-N- hydroxybenzamide

R¹ = ethyl R² = 2-phenylethyl R³ = hydrogen R⁴ = hydrogen R⁵ = hydrogenR⁶ = 4-(N- hydroxyaminocarbonyl) benzyl 5a 4-(2-ethyl-3,4-dihydro-4-oxo-3- phenethylquinazolin-8- yl)-N-hydroxybenzamide

R¹ = ethyl R² = 2-phenylethyl R³ = hydrogen R⁴ = hydrogen R⁵ = hydrogenR⁶ = 4-(N- hydroxyaminocarbonyl) phenyl 6a (2E)-N-(2-aminophenyl)-3-(3,4-dihydro-2-methyl- 4-oxo-3- phenethylquinazolin-7- yl)acrylamide

R¹ = methyl R² = 2-phenylethyl R³ = hydrogen R⁴ = hydrogen R⁵ =(2E)-3-N-(2- aminophenyl)-3- oxo-propenyl R⁶ = hydrogen Formula(II) 2a(2E)-3-(2-ethyl-6-fluoro- 3,4-dihydro-4-oxo-3- phenethylquinazolin-7-yl)-N-hydroxyacrylamide

R¹ = ethyl R² = 2-phenylethyl R³ = hydrogen R⁴ = fluoro R⁵ = (2E)-3-N-hydroxyamino-3- oxo-propenyl R⁶ = hydrogen Formula(III) 3a(2E)-3-(2-ethyl-7-fluoro- 3,4-dihydro-4-oxo-3- phenethylquinazolin-6-yl)-N-hydroxyacrylamide

R¹ = ethyl R² = 2-phenylethyl R³ = hydrogen R⁴ = (2E)-3-N-hydroxyamino-3- oxo-propenyl R⁵ = fluoro R⁶ = hydrogen 3b(2E)-3-(7-chloro-2-ethyl- 3,4-dihydro-4-oxo-3- phenethylquinazolin-6-yl)-N-hydroxyacrylamide

R¹ = ethyl R² = 2-phenylethyl R³ = hydrogen R⁴ = (2E)-3-N-hydroxyamino-3- oxo-propenyl R⁵ = chloro R⁶ = hydrogen

-   R¹ is hydrogen, methyl, ethyl, cyclopropyl, or isopropyl;-   R² is phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl,    2-(1H-indol-3-yl)ethyl, 2-(4-fluorophenyl)ethyl, or    2-(4-methoxyphenyl)ethyl;-   R³ is hydrogen or (2E)-3-N-hydroxyamino-3-oxo-propenyl;-   R⁴ is hydrogen, fluoro, (2E)-3-N-hydroxyamino-3-oxo-propenyl, or    4-(N-hydroxyaminocarbonyl)benzyl:-   R⁵ is hydrogen, (2E)-3-N-hydroxyamino-3-oxo-propenyl,    4-(N-hydroxyaminocarbonyl)benzyl, or    (2E)-3-N-(2-aminophenyl)-3-oxo-propenyl; and-   R⁶ is hydrogen, (2E)-3-N-hydroxyamino-3-oxo-propenyl,    4-(N-hydroxyaminocarbonyl)phenyl, or    4-(N-hydroxyaminocarbonyl)benzyl.

The foregoing description of the exemplary embodiments of the inventionhas been presented only for the purposes of illustration and descriptionand is not intended to be exhaustive or to limit the invention to theprecise forms disclosed. Many modifications and variations are possiblein light of the above teaching.

The embodiments and examples were chosen and described in order toexplain the principles of the invention and their practical applicationso as to enable others skilled in the art to utilize the invention andvarious embodiments and with various modifications as are suited to theparticular use contemplated. Alternative embodiments will becomeapparent to those skilled in the art to which the present inventionpertains without departing from its spirit and scope. Accordingly, thescope of the present invention is defined by the appended claims ratherthan the foregoing description and the exemplary embodiments describedtherein

Some references, which may include patents, patent applications andvarious publications, are cited and discussed in the description of thisinvention. The citation and/or discussion of such references is providedmerely to clarify the description of the present invention and is not anadmission that any such reference is “prior art” to the inventiondescribed herein All references cited and discussed in thisspecification are incorporated herein by reference in their entiretiesand to the same extent as if each reference was individuallyincorporated by reference.

What is claimed is:
 1. A compound having the structure

or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug,or a metabolite thereof, wherein R¹ is hydrogen (C₁-C₆)alkyl, or(C₃-C₆)cycloalkyl; R² is (C₆-C₁₈)aryl, (C₆-C₁₈)aryl(C₁-C₆)alkyl,(C₃-C₁₈)heteroaryl(C₁-C₆)alkyl, halo(C₆-C₁₈)aryl(C₁-C₆)alkyl, or(C₁-C₆)alkoxy(C₆-C₁₈)aryl(C₁-C₆)alkyl; R³ is hydrogen orN-hydroxyamino-oxo(C₂-C₆)alkenyl; R⁴ is hydrogen, halogen.N-hydroxyamino-oxo(C₂-C₆)alkenyl, or N-hydroxyaminocarbonyl(C₆-C₁₈)aryl(C₁-C₆)alkylene; R⁵ is hydrogen, halogen,N-hydroxyamino-oxo(C₂-C₆)alkenyl,N-hydroxyaminocarbonyl(C₆-C₁₈)aryl(C₁-C₆)alkylene, oramino(C₆-C₁₈)aryl-oxo(C₂-C₆)alkenyl; and R⁶ is hydrogen,N-hydroxyamino-oxo(C₂-C₆)alkenyl, N-hydroxyamino(C₆-C₁₈)aryl (C₁-C₆)alkylene or N-hydroxy amino carbonyl(C₆-C₁₈)aryl(C₁-C₆)alkylene.
 2. Thecompound of claim 1, wherein R¹ is hydrogen, methyl, ethyl, cyclopropyl,or isopropyl; R² is phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl,2-(1H-indol-3-yl)ethyl, 2-(4-fluorophenyl)ethyl, or2-(4-methoxyphenyl)ethyl; R³ is hydrogen or(2E)-3-N-hydroxyamino-3-oxo-propenyl; R⁴ is hydrogen, fluoro,(2E)-3-N-hydroxyamino-3-oxo-propenyl, or4-(N-hydroxyaminocarbonyl)benzyl; R⁵ is hydrogen,(2E)-3-N-hydroxyamino-3-oxo-propenyl, 4-(N-hydroxyaminocarbonyl)benzyl,or (2E)-3-N-(2-aminophenyl)-3-oxo-propenyl; and R⁶ is hydrogen,(2E)-3-N-hydroxyamino-3-oxo-propenyl, 4-(N-hydroxyaminocarbonyl)phenyl,or 4-(N-hydroxyaminocarbonyl)benzyl, or a salt thereof.
 3. The compoundof clam 2, wherein R¹ is hydrogen, methyl, ethyl, cyclopropyl, orisopropyl; R² is phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl,2-(1H-indol-3-yl)ethyl, 2-(4-fluorophenyl)ethyl, or2-(4-methoxyphenyl)ethyl; R³ is hydrogen or(2E)-3-N-hydroxyamino-3-oxo-propenyl; R⁴ is hydrogen, fluoro,(2E)-3-N-hydroxyamino-3-oxo-propenyl, or4-(N-hydroxyaminocarbonyl)benzyl; R⁵ is hydrogen,(2E)-3-N-hydroxyamino-3-oxo-propenyl, 4-(N-hydroxyaminocarbonyl)benzyl,or (2E)-3-N-(2-aminophenyl)-3-oxo-propenyl; and R⁶ is hydrogen,(2E)-3-N-hydroxyamino-3-oxo-propenyl, 4-(N-hydroxyaminocarbonyl)phenyl,or 4-(N-hydroxyaminocarbonyl)benzyl, or a salt thereof.
 4. The compoundof claim 2, wherein R¹ is ethyl; R² is 2-phenylethyl; R³ is hydrogen; R⁴is fluoro; R⁵ is (2E)-3-N-hydroxyamino-3-oxo-propenyl; and R⁶ ishydrogen, or a salt thereof.
 5. The compound of claim 2, wherein R¹ isethyl; R² is 2-phenylethyl; R³ is hydrogen; R⁴ is(2E)-3-N-hydroxyamino-3-oxo-propenyl; R⁵ is chloro or fluoro; and R⁶ ishydrogen, or a salt thereof.
 6. The compound of claim 2, wherein thecompound is selected from the group consisting of(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-5-yl)-N-hydroxyacrylamide,(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-6-yl)-N-hydroxyacrylamide,(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-8-yl)-N-hydroxyacrylamide(2E)-3-(3-benzyl-3,4-dihydro-2-methyl-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(3-(2-(1H-indol-3-yl)ethyl)-3,4-dibydro-2-methyl-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(2-ethyl-3,4-dihydro-4-oxo-3-(3-phenylpropyl)quinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(2-cyclopropyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(3,4-dihydro-2-isopropyl-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(3-(4-methoxyphenethyl)-2-ethyl-3,4-dihydro-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide,(2E)-3-(3-(4-fluorophenethyl)-2-ethyl-3,4-dihydro-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide,4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)methyl)-N-hydroxybenzamide,4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)methyl)-N-hydroxybenzamide,4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-8-yl)methyl)-N-hydroxybenzamide,4-(2-ethyl-3,4-dihydro-4-oxo-3-phethylquinazol-8-yl)-N-hydroxybenzamide,and(2E)-N-(2-aminophenyl)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenethylquinazolin-7-yl)acrylamide.7. The compound of claim 2, wherein the compound is(2E)-3(2-ethyl-6-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,or a salt thereof.
 8. The compound of claim 2, wherein the compound is(2E)-3-(2-ethyl-7-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide,(2E)-3-(7-chloro-2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-hydroxyacrylamide,or a salt thereof.
 9. A composition comprising a therapeuticallyeffective amount of the compound of claim 1, or a pharmaceuticallyacceptable salt, a solvate or hydrate, a prodrug, or a metabolitethereof, and a pharmaceutically acceptable carrier or vehicle.
 10. Amethod of treating a tumor disease associated with deregulation of theactivity of historic deacetylases, comprising administering to a subjectin need thereof a therapeutically effective amount of the compound claim1 or a pharmaceutically acceptable salt, a solvate or hydrate, aprodrug, or a metabolite thereof, and a pharmaceutically acceptablecarrier or vehicle.
 11. The method of claim 10, wherein the tumordisease associated to the deregulation of the activity of histonedeacetylases is at least one selected from the group consisting ofpancreatic carcinoma, hepatocellular carcinoma, colon tumor, breasttumor, prostate tumor, lymphoma and cutaneous tumor.
 12. The method ofclaim 11, wherein the cutaneous tumor disease is at least one selectedfrom the group consisting or melanomas and basal carcinomas.
 13. Themethod of claim 10, wherein the tumor is at least one selected from thegroup consisting of breast cancer, colon cancer, large cell lung cancer,adenocarcinoma of the lung, small cell lung cancer, stomach cancer,liver cancer, ovary adenocarcinoma, pancreas carcinoma, prostatecarcinoma, promylocytic leukemia, chronic myelocytic leukemia, and acutelymphocytic leukemia.
 14. A method for treating a neurodegenerativedisease, comprising administering to a subject in need thereof atherapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt, a solvate or hydrate a prodrug, or ametabolite thereof, and a pharmaceutically acceptable carrier orvehicle, wherein the neurodegenerative disease is at least one selectedfrom the group consisting of Huntington's diseases (HD). Alzheimer'sdisease (AD), Parkinson's disease (PD), and Amyotrophic lateralsclerosis (ALS).
 15. A composition comprising a therapeuticallyeffective amount of the compound of claim 2, or a pharmaceuticallyacceptable salt, a solvate or hydrate, a prodrug or a metabolitethereof, and a pharmaceutically acceptable carrier or vehicle.
 16. Acomposition comprising a therapeutically effective amount of thecompound of claim 3, or a pharmaceutically acceptable salt, a solvate orhydrate, a prodrug, or a metabolite thereof, and a pharmaceuticallyacceptable carrier or vehicle.
 17. A composition comprising atherapeutically effective amount of the compound of claim 4, or apharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or ametabolite thereof, and a pharmaceutically acceptable carrier orvehicle.
 18. A composition comprising a therapeutically effective amountof the compound of claim 5, or a pharmaceutically acceptable salt, asolvate or hydrate, a prodrug, or a metabolite thereof, and apharmaceutically acceptable carrier or vehicle.
 19. A compositioncomprising a therapeutically effective amount of the compound of claim6, or a pharmaceutically acceptable salt, a solvate or hydrate, aprodrug, or a metabolite thereof and a pharmaceutical acceptable carrieror vehicle.
 20. A method for treating a disease or condition whereininhibition of HDAC provides a benefit, comprising administering to asubject in need thereof a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt, a solvate orhydrate, a prodrug, or a metabolite thereof, and a pharmaceuticallyacceptable carrier or vehicle.